Transarterial chemoembolization using degradable starch microspheres and iodized oil in the treatment of advanced hepatocellular carcinoma: evaluation of tumor response, toxicity, and survival

BACKGROUND: In a multidisciplinary conference patients with advanced non-resectable hepatocellular carcinoma (HCC) were stratified according to their clinical status and tumor extent to different regional modalities or to best supportive care. The present study evaluated all patients who were stratified to repeated transarterial chemoembolization (TACE) from 1999 until 2003 in terms of tumor response, toxicity, and survival. A moderate embolizing approach was chosen using a combination of degradable starch microspheres (DSM) and iodized oil (Lipiodol) in order to combine anti-tumoral efficiency and low toxicity. METHODS: Fourty-seven patients were followed up prospectively. TACE treatment consisted of cisplatin (50 mg/m2), doxorubicin (50 mg/m2), 450-900 mg DSM, and 5-30 ml Lipiodol. DSM and Lipiodol were administered according to tumor vascularization. Patient characteristics,toxicity, and complications were outlined. In multivariate regression analyses of pre-treatment variables from a prospective database, predictors for tumor response and survival after TACE were determined. RESULTS: 112 TACE courses were performed (2.4±1.5 courses per patient). Mean maximum tumor size was 75 (± 43) mm, in 68% there was bilobar disease. Best response to TACE treatment was: progressive disease (PD) 9%, stable disease (SD) 55%, partial remission (PR) 36%, and complete remission (CR) 0%. Multivariate regression analyses identified tumor size ≤75 mm, tumor number ≤5, and tumor hypervascularization as predictors for PR. The overall 1-, 2-, and 3-year-survival rates were 75%, 59%, and 41%, respectively, and the median survival was 26 months. Low α-fetoprotein levels (<400 ng/ml) (Odds ratio=3.3) and PR as best response to TACE (Odds ratio=6.7) were significantly associated with long term survival (>30 months, R2=36%). Grade 3 toxicity occurred in 7.1% (n=8), and grade 4 toxicity in 3.6% (n=4) of all courses in terms of reversible leukopenia and thrombocytopenia. The incidence of major complications was 5.4% (n=6). All complications were managed conservatively. The mortality within 6 weeks after TACE was 2.1% (one patient). CONCLUSIONS: DSM and Lipiodol were combined successfully in the palliative TACE treatment of advanced HCC resulting in high rates of tumor response and survival at limited toxicity. Favourable tumor response was associated with tumor extent and vascularization. TACE using DSM and Lipiodol can be considered a suitable palliative measure in patients who might not tolerate long acting embolizing agents.

Combination of repeated single-session percutaneous ethanol injection and transarterial chemoembolisation compared to repeated single-session percutaneous ethanol injection in patients with non-resectable hepatocellular carcinoma

AIM： To evaluate the treatment effect of percutaneous ethanol injection （PEI） for patients with advanced, non-resectable HCC compared with combination of transarterial chemoembolisation （TACE） and repeated single-session PEI, repeated single-session PEI alone, repeated TACE alone, or best supportive care. METHODS： All patients who received PEI treatment during the study period were included and stratified to one of the following treatment modalities according to physical status and tumor extent： combination of TACE and repeated single-session PEI, repeated single-session PEI alone, repeated TACE alone, or best supportive care. Prognostic value of clinical parameters including Okuda-classification, presence of portal vein thrombosis, presence of ascites, number of tumors, maximum tumor diameter, and serum cholinesterase （CHE）, as well as Child-Pugh stage, α-fetoprotein （AFP）, fever, incidence of complications were assessed and compared between the groups. Survival was determined using Kaplan-Meier and multivariate regression analyses.

Direct ex vivo analysis of dendritic cells in patients with hepatocellular carcinoma

AIM： To analyze the phenotype and function of dendritic cells （DC） from patients with hepatocellular carcinoma （HCC） in order to understand their role in this disease. METHODS： Myeloid dendritic cells were enumerated in peripheral blood of HCC patients. CD80, CD83, CD86 and HLA-DR expression on naive and stimulated myeloid dendritic cells from peripheral blood were analyzed. Myeloid dendritic cells were isolated from peripheral blood and their function was tested. Phagocytosis was analyzed using FITC-dextran beads, peptide specific stimulation, the capacity to stimulate allogeneic T cells and secretion of cytokines upon poly dZ：dC was tested. RESULTS： Myeloid dendritic cells were reduced in patients with HCC. No differences in CD80, CD83, CD86 and HLA-DR expression were found on naive and stimulated myeloid dendritic cells from HCC patients and healthy controls. Normal phagocytosis or stimulation of peptide specific T cells was observed in contrast to an impaired allo-stimulatory capacity and a reduced IL-12 secretion. CONCLUSION： Impaired IL-12 production of mDCs in patients could lead to an impaired stimulatory capacity of naive T cells suggesting that IL-12 directed therapies may enhance tumor specific immune responses in HCC patients.

FibroSURE^(TM) and FibroScan~ in relation to treatment response in chronic hepatitis C virus

AIM:To compare histological endpoint assessment using noninvasive alternatives to biopsy during treatment in a chronic hepatitis C virus(HCV)cohort.METHODS:Patients with chronic HCV were randomized to receive interferon-based therapy for 24(genotypes 2/3)or 48(genotype 1)wk.FibroSURE～TM(FS)was assessed at baseline and at week-12 post-treatment follow-up.Baseline biopsy for METAVIR was assessed by a single pathologist.FibroScan～ transient elastogra-phy(TE)was performed during treatment in a patient subset.RESULTS:Two thousand and sixty patients(n = 253 in Asia)were classif ied as METAVIR F0-1(n = 1682)or F2-4(n = 378).For F2-4,FS(n = 2055)had sensitiv-ity and specif icity of 0.87 and 0.61,respectively,with area under the receiver-operating curve of 0.82;corre-sponding values for TE(n = 214)and combined FS/TE(n = 209)were 0.77,0.88 and 0.88,and 0.93,0.68 and 0.88.Overall FS/TE agreement for F2-4 was 71%(κ = 0.41)and higher in Asians vs non-Asians(κ = 0.86 vs 0.35;P < 0.001).Combined FS/TE had 97% accuracy in Asians(n = 33).Baseline FS(0.38 vs 0.51,P < 0.001)and TE(8.0 kPa vs 11.9 kPa,P = 0.006)scores were lower in patients with sustained virological response than in nonresponders,and were maintained through follow-up.CONCLUSION:FS and TE may reliably differentiate mild from moderate-advanced disease,with a potential for high diagnostic accuracy in Asians with chronic HCV.

Successful treatment of cervical esophageal leakage by endoscopic-vacuum assisted closure therapy

AIM: To evaluate the efficacy and safety of endoscopic-vacuum assisted closure (E-VAC) therapy in the treatment of cervical esophageal leakage. METHODS: Between May and November 2012, three male patients who developed post-operative cervical esophageal leakage were treated with E-VAC therapy. One patient had undergone surgical excision of a pharyngo-cervical liposarcoma with partial esophageal resection, and the other two patients had received surgical treatment for symptomatic Zenker's diverticulum. Following endoscopic verification of the leakage, a trimmed polyurethane sponge was fixed to the distal end of a nasogastric silicone tube and endoscopically positioned into the wound cavity, and with decreasing cavity size the sponge was positioned intraluminally to cover the leak. Continuous suction was applied, and the vacuum drainage system was changed twice a week.RESULTS: The initial E-VAC placement was technically successful for all three patients, and complete closure of the esophageal leak was achieved without any procedure-related complications. In all three patients, the insufficiencies were located either above or slightly below the upper esophageal sphincter. The median duration of the E-VAC drainage was 29 d (range: 19-49 d), with a median of seven sponge exchanges (range: 5-12 sponge exchanges). In addition, the E-VAC therapy reduced inflammatory markers to within normal range for all three patients. Two of the patients were immediately fitted with a percutaneous enteral gastric feeding tube with jejunal extension, and the third patient received parenteral feeding. All three patients showed normal swallow function and no evidence of stricture after completion of the E-VAC therapy. CONCLUSION: E-VAC therapy for cervical esophageal leakage was well tolerated by patients. This safe and effective procedure may significantly reduce morbidity and mortality following cervical esophageal leakage.

Homologous recombination mediates stable Fah gene integration and phenotypic correction in tyrosinaemia mouse-model

AIM To stably correct tyrosinaemia in proliferating livers of fumarylacetoacetate-hydrolase knockout(Fah-/-) mice by homologous-recombination-mediated targeted addition of the Fah gene.METHODS C57 BL/6 Fah?exon5 mice served as an animal model for human tyrosinaemia type 1 in our study. The vector was created by amplifying human Fah c DNA including the TTR promoter from a lentivirus plasmid as described. The Fah expression cassette was flanked by homologous arms(620 bp and 749 bp long) of the Rosa26 gene locus. Mice were injected with 2.1 × 108 VP of this vector(r AAV8-ROSA26.HAL-TTR.FahROSA26.HAR) via the tail vein. Mice in the control group were injected with 2.1 × 108 VP of a similar vector but missing the homologous arms(r AAV8-TTR.Fah). Primary hepatocytes from Fah-/-recipient mice, treated with our vectors, were isolated and 1 × 106 hepatocytes were transplanted into secondary Fah-/-recipient mice by injection into the spleen. Upon either vector application or hepatocyte transplantation NTBC treatment was stopped in recipient mice. RESULTS Here, we report successful HR-mediated genome editing by integration of a Fah gene expression cassette into the "safe harbour locus" Rosa26 by recombinant AAV8. Both groups of mice showed long-term survival, weight gain and FAH positive clusters as determined by immunohistochemistry analysis of liver sections in the absence of NTBC treatment. In the group of C57 BL/6 Fah?exon5 mice, which have been transplanted with hepatocytes from a mouse injected with r AAV8-ROSA26.HAL-TTR.Fah-ROSA26.HAR 156 d before, 6 out of 6 mice showed long-term survival, weight gain and FAH positive clusters without need for NTBC treatment. In contrast only 1 out 5 mice, who received hepatocytes from r AAV8-TTR.Fah treated mice, survived and showed few and smaller FAH positive clusters. These results demonstrate that homologous recombinationmediated Fah gene transfer corrects the phenotype in a mouse model of human tyrosinaemia type 1(Fah-/-mice) and is long lasting in a proliferating state of the liver as shown by withdrawal of NTBC treatment and serial transplantation of isolated hepatocytes from primary Fah-/-recipient mice into secondary Fah-/-recipient mice. This long term therapeutic efficacy is clearly superior to our control mice treated with episomal r AAV8 gene therapy approach.CONCLUSION HR-mediated r AAV8 gene therapy provides targeted transgene integration and phenotypic correction in Fah-/-mice with superior long-term efficacy compared to episomal r AAV8 therapy in proliferating livers.

Changes of duplex parameters and splenic size in liver transplant recipients during a long period of observation

AIM: To assess the changes of portal and arterial velocities, resistance index, spleen and liver size during a long observation period (13.7 years) after orthotopic liver transplantation (OLT).METHODS: Two hundred and sixty patients were recruited retrospectively for this study and divided into groups with defined time intervals after OLT. The cross-sectional changes of portal and arterial velocities,resistance index, spleen and liver size between the defined time intervals were studied. The complications detected by ultrasound were compared to gold standard methods.RESULTS: The mean values for liver size were all within the normal range. The splenic size decreased between the time intervals 100 and 1 000 d after OLT (t;P＜0.01).While portal and arterial flow velocities decreased up to 5.5 years (t; portal velocity P＜0.01, maximal systolic velocity P=0.05, maximal end diastolic velocity P＜0.01),RI increased during this interval (t:P＜0.01). Higher RIvalues were found in older patients (r = 0.24, P＜0.001).CONCLUSION: The arterial and portal velocities show adaptation processes continuing over the course of many years after OLT and are reported for the first time. The vascular complications detected by ultrasound occur mostly up to 100 d after OLT.